The object of this study is to learn the mechanisms by which fish oil fatty acids can affect the responses of cells to normal agonists and noxious agents. There is ample evidence that the long chain polyunsaturated n-3 or n-6 fatty acids (PUFA) can affect differently many cellular processes. Diets containing fish or fish oils alter some inflammatory, immunologic, and atherosclerotic processes. These effects could be due to the differences in eicosanoids, docosanoids, leukotrienes, lipoxins, or P450 metabolites produced from eicosapentaenoic acid, EPA (C20:5n-3), and docosahexaenoic acid, DHA (C22:6n-3), when they replace arachidonic acid, AA (C20:4n-6) in the sn-2 position of membrane phospholipids. Alternatively, they could be due directly to changes in the function of membrane-bound proteins (enzymes, receptors, transport channels) resulting from enrichment of their phospholipid microenvironment with EPA and DHA. How changes in cellular functions are induced by these subtle changes of phospholipid fatty acids is not yet understood. We have shown that enriching isolated rat cardiac myocytes with EPA or DHA (in contrast to n-6 AA) in vitro completely protects the myocytes against toxicity from a high concentration of cardiac glycosides (10-4 M ouabain). EPA or DHA prevents lethal levels of cytosolic calcium in response to toxic concentrations of ouabain by blocking entry of calcium into the myocytes. The mechanism of this protective effect can be clarified by further studies in our model systems. Of the half million deaths from heart attacks annually in the United States, 300,000 deaths will occur before the victims get to a hospital, according to the American Heart Association. The great majority of these "sudden deaths" are due to ventricular fibrillation. Thus our studies to understand the mechanisms by which the fish oil fatty acids prevent arrhythmias of cardiac myocytes may have potential public health importance.